Binding of the HIV-1 envelope glycoprotein (Env, gp120-gp41) to CD4 and coreceptors initiates a series of conformational changes that are the heart of the fusion machinery leading to viral entry1. The elucidation of the nature of the Env conformational changes is not only a clue to the mechanism of HIV type 1 (HIV-1) entry but may also provide new tools for the development of inhibitors and vaccines.2,3 It has been proposed that the interaction of coreceptor molecules with the Env-CD4 complex leads to intermediate Env conformations that may include structures conserved among various HIV 1 isolates that could be used as vaccines4,5. Of the four known potent broadly neutralizing antibodies (b127, 2F58,9, 2G1210, and 4E10/Z1311), none has a receptor-inducible epitope.
No single broadly cross-reactive monoclonal antibody with potent neutralization activity for all primary HIV isolates has been isolated and characterized. Typically, monoclonal antibodies against CD4-inducible epitopes, such as 17b and CG10, are only weakly neutralizing against primary isolates16, suggesting that CD4-inducible epitopes on gp120 may not serve as targets for potent broadly neutralizing antibodies.
It is an object of the present invention to provide antibodies to receptor-inducible epitopes, wherein the antibodies exhibit high affinity of binding of HIV and neutralizing activity. The antibodies can be used, alone or in combination with other active agents or as fusion proteins or conjugates with other active agents, to inhibit HIV and as tools to dissect mechanisms of HIV cellular entry. This and other objects and advantages of the present invention, as well as additional inventive features, will become apparent from the detailed description provided herein.